Orlistat, tetrahydrolipostatin, is a hypolipaemic lipstatin derivative, presently under development by Roche under the tradename Xenical®. Orlistat is a potent and selective inhibitor of pancreatic lipase. It also creates a fat phase in the intestine and removes endogenous cholesterol from bile in the intestine (Scrip, 1993, 1850, 12 & 1996, 2135, 22; Ann Rep, Roche, 1993). The lipase inhibitors act within the GI tract to inhibit the enzymes which hydrolyze dietary fat to glycerol and fatty acids. This hydrolysis is the required first step for fat digestion, and enables the absorption of lipids and fats, and their subsequent utilization for energy metabolism. Inhibition of fat digestion by lipase inhibitors such as orlistat, prevents fat absorption and hence, the availability of calories from ingested lipid.
Orlistat prevents the absorption of about one third of the fat contained in food (Ann Rep, Roche, 1995). The drug has undergone numerous placebo-controlled clinical studies, involving over 5000 obese patients. Orlistat resulted in significant weight loss and had no major adverse side-effects. During the first year of a two year study, 3-times as many patients on orlistat (with a moderately reduced calorie diet) lost 10% or more body weight as compared to patients treated with placebo and diet alone. Most patients who continued into the 2nd year of the study kept the lost weight off (Scrip, 1996, 2188, 17; Press release, Roche, May 1997). The drug is also being studied in patients with Type II diabetes (Ann Rep, Roche, 1992). The first year results of a 2 year study have shown that 228 patients receiving orlistat 3× daily as well as following a mildly hypocaloric diet have lost 65% more weight than the placebo controlled group, with almost ⅓ having lost >10% of their bodyweight (Scrip, 1996, 2135, 22).
In diet-induced obese rats, orlistat at 27 mg/kg/day caused a marked loss of body weight (65 g) and a decrease in carcass fat (54 g), despite occurrence of mild hyperphagia (1 1%). Fat absorption decreased from 93-94% to 17-19%. Orlistat—treated rats showed decreases in liver (13%) and retroperitoneal (RP) pad weight and an increase in small (27%) and large (38%) intestine weight (Fed Proc, 1987, 46, 1537).
The class of lipstatin inhibitors, which includes orlistat, inhibit enzymatic cleavage of fat within the intestinal lumen and largely prevents fat absorption from the intestine. Lipstatin inhibitors may be added at 0.1-100 mg ranges as a dietary additive to feedstuffs (esp. for dogs or cats) to prevent or treat adiposity and to optimize the weight of the animal. Use of these inhibitors with water insoluble fiber may further reduce fat resorption and is the subject of U.S. Pat. No. 5,540,917. Dose of orlistat plus water insoluble fiber reduces absorption of fat from the feedstuff by 1-100 (esp. 40-70) %. U.S. Pat. No. 5,540,917 does however, require large amounts of crude fiber to fat as the desired fiber content is 2-3× the fat content intake.
The lipase inhibitors act peripherally to inhibit fat digestion, and lack CNS side-effects. Their major side-effect is the potential to cause steatorrhea, anal oil leakage and incontinence, flatulence, and GI distress.
There exists in the art, the need to develop a product which would allow human patients to sustain a treatment regiment of the lipostatin derivatives, but reduce the potential side effects, such as anal leakage, or at least minimize them. A combination a product which would reduce these side effects would also provide for an easily administered product, which is convenient to take and transport.